title: p600 Plays Essential Roles in Fetal Development.
abstract: p600 is a multifunctional protein implicated in cytoskeletal organization, integrin-mediated survival signaling, calcium-calmodulin signaling and the N-end rule pathway of ubiquitin-proteasome-mediated proteolysis. While push, the Drosophila counterpart of p600, is dispensable for development up to adult stage, the role of p600 has not been studied during mouse development. Here we generated p600 knockout mice to investigate the in vivo functions of p600. Interestingly, we found that homozygous deletion of p600 results in lethality between embryonic days 11.5 and 13.5 with severe defects in both embryo and placenta. Since p600 is required for placental development, we performed conditional disruption of p600, which deletes selectively p600 in the embryo but not in the placenta. The conditional mutant embryos survive longer than knockout embryos but ultimately die before embryonic day 14.5. The mutant embryos display severe cardiac problems characterized by ventricular septal defects and thin ventricular walls. These anomalies are associated with reduced activation of FAK and decreased expression of MEF2, which is regulated by FAK and plays a crucial role in cardiac development. Moreover, we observed pleiotropic defects in the liver and brain. In sum, our study sheds light on the essential roles of p600 in fetal development.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America ; Translational Research Unit and Department of Molecular Pathology, Tokyo Medical University, Shinjuku, Tokyo, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakaya
authors.forename: Kei-Ichiro
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Camille
authors.initials: C
authors.lastname: Belzil
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rietsch
authors.forename: Qunyan
authors.initials: Q
authors.lastname: Yu
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Mizuno
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Yan
authors.initials: Y
authors.lastname: Geng
authors.forename: Minh Dang
authors.initials: MD
authors.lastname: Nguyen
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakatani
mesh_terms: D000818:Animals; D005071:Evoked Potentials / Q000235:genetics; D047109:Fetal Development / Q000502:physiology*; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout